tbuckley/cabot-search huggingface dataset:
First-in-human in vivo genome editing via AAV-zinc-finger nucleases for mucopolysaccharidosis I/II and hemophilia B
Authors: Paul Harmatz, Carlos E. Prada, Barbara K. Burton, Heather Lau, Craig M. Kessler, Liching Cao, Marina Falaleeva, Andres G. Villegas, Jennifer Zeitler, Kathleen Meyer, Weston Miller, Cheryl Wong Po Foo, Sagar Vaidya, Wendy Swenson, Lisa H. Shiue, Didier Rouy, Joseph Muenzer
Journal: Molecular Therapy (2022)

Zinc-finger nuclease (ZFN)-based in vivo genome editing is a novel treatment that can potentially provide lifelong protein replacement with single intravenous administration. Three first-in-human open-label ascending single-dose phase 1/2 studies were performed in parallel (starting November 2017) primarily to assess safety and tolerability of ZFN in vivo editing therapy in mucopolysaccharidosis I (MPS I) (n = 3), MPS II (n = 9), and hemophilia B (n = 1). Treatment was well tolerated with no serious treatment-related adverse events. At the 1e13 vg/kg dose, evidence of genome editing was detected through albumin-transgene fusion transcripts in liver for MPS II (n = 2) and MPS I (n = 1) subjects. The MPS I subject also had a transient increase in leukocyte iduronidase activity to the lower normal range. At the 5e13 vg/kg dose, one MPS II subject had a transient increase in plasma iduronate-2-sulfatase approaching normal levels and one MPS I subject approached mid-normal levels of leukocyte iduronidase activity with no evidence of genome editing. The hemophilia B subject was not able to decrease use of factor IX concentrate; genome editing could not be assessed. Overall, ZFN in vivo editing therapy had a favorable safety profile with evidence of targeted genome editing in liver, but no long-term enzyme expression in blood. Zinc-finger nuclease (ZFN)-based in vivo genome editing is a novel treatment that can potentially provide lifelong protein replacement with single intravenous administration. Three first-in-human open-label ascending single-dose phase 1/2 studies were performed in parallel (starting November 2017) primarily to assess safety and tolerability of ZFN in vivo editing therapy in mucopolysaccharidosis I (MPS I) (n = 3), MPS II (n = 9), and hemophilia B (n = 1). Treatment was well tolerated with no serious treatment-related adverse events. At the 1e13 vg/kg dose, evidence of genome editing was detected through albumin-transgene fusion transcripts in liver for MPS II (n = 2) and MPS I (n = 1) subjects. The MPS I subject also had a transient increase in leukocyte iduronidase activity to the lower normal range. At the 5e13 vg/kg dose, one MPS II subject had a transient increase in plasma iduronate-2-sulfatase approaching normal levels and one MPS I subject approached mid-normal levels of leukocyte iduronidase activity with no evidence of genome editing. The hemophilia B subject was not able to decrease use of factor IX concentrate; genome editing could not be assessed. Overall, ZFN in vivo editing therapy had a favorable safety profile with evidence of targeted genome editing in liver, but no long-term enzyme expression in blood.
Alternative strategies to increase the immunogenicity of COVID-19 vaccines in kidney transplant recipients not responding to two or three doses of an mRNA vaccine (RECOVAC): a randomised clinical trial
Authors: Marcia M L Kho, A Lianne Messchendorp, Sophie C Frölke, Celine Imhof, Vera JCH Koomen, S Reshwan K Malahe, Priya Vart, Daryl Geers, Rory D de Vries, Corine H GeurtsvanKessel, Carla C Baan, Renate G van der Molen, Dimitri A Diavatopoulos, Ester B M Remmerswaal, Debbie van Baarle, Rob van Binnendijk, Gerco den Hartog, Aiko P J de Vries, Ron T Gansevoort, Frederike J Bemelman, Marlies E J Reinders, Jan-Stephan F Sanders, Luuk B Hilbrands, Alferso C. Abrahams, Marije C. Baas, Pim Bouwmans, Marc A.G.J. ten Dam, Lennert Gommers, Dorien Standaar, Marieke van der Heiden, Yvonne M.R. Adema, Marieken J. Boer-Verschragen, Wouter B. Mattheussens, Ria H.L.A. Philipsen, Djenolan van Mourik, Susanne Bogers, Laura L.A. van Dijk, Nynke Rots, Gaby Smits, Marjan Kuijer, Marc H. Hemmelder
Journal: The Lancet Infectious Diseases (2022)
Economic evaluations of fall prevention exercise programs: a systematic review
Authors: Marina B Pinheiro, Catherine Sherrington, Kirsten Howard, Patrick Caldwell, Anne Tiedemann, Belinda Wang, Juliana S Oliveira, Andreia Santos, Fiona C Bull, Juana F Willumsen, Zoe A Michaleff, Sarah Ferguson, Eleesheva Mayo, Nicola J Fairhall, Adrian E Bauman, Sarah Norris
Journal: British Journal of Sports Medicine (2022)

Objective To investigate cost-effectiveness and costs of fall prevention exercise programmes for older adults. Design Systematic review. Data sources Medline, Embase, Web of Science, Scopus, National Institute for Health Research Economic Evaluation Database, Health Technology Assessment database, Tufts Cost-Effectiveness Analysis Registry, Research Papers in Economics and EconLit (inception to May 2022). Eligibility criteria for study selection Economic evaluations (trial-based or model-based) and costing studies investigating fall prevention exercise programmes versus no intervention or usual care for older adults living in the community or care facilities, and reporting incremental cost-effectiveness ratio (ICER) for fall-related outcomes or quality-adjusted life years (QALY, expressed as cost/QALY) and/or intervention costs. Results 31 studies were included. For community-dwelling older adults (21 economic evaluations, 6 costing studies), results ranged from more effective and less costly (dominant) interventions up to an ICER of US$279 802/QALY gained and US$11 986/fall prevented (US$ in 2020). Assuming an arbitrary willingness-to-pay threshold (US$100 000/QALY), most results (17/24) were considered cost-effective (moderate certainty). The greatest value for money (lower ICER/QALY gained and fall prevented) appeared to accrue for older adults and those with high fall risk, but unsupervised exercise appeared to offer poor value for money (higher ICER/QALY). For care facilities (two economic evaluations, two costing studies), ICERs ranged from dominant (low certainty) to US$35/fall prevented (moderate certainty). Overall, intervention costs varied and were poorly reported. Conclusions Most economic evaluations investigated fall prevention exercise programmes for older adults living in the community. There is moderate certainty evidence that fall prevention exercise programmes are likely to be cost-effective. The evidence for older adults living in care facilities is more limited but promising. PROSPERO registration number PROSPERO 2020 CRD42020178023.
Molecular Determinants of Clinical Outcomes In a Real-World Diffuse Large B-cell Lymphoma Population
Authors: Waleed Alduaij, Brett J Collinge, Susana Ben-Neriah, Aixiang Jiang, Laura K Hilton, Merrill Boyle, Barbara Meissner, Lauren C. Chong, Tomoko Miyata-Takata, Graham W. Slack, Pedro Farinha, Jeffrey W Craig, Andrew Lytle, Kerry J. Savage, Diego Villa, Alina S. Gerrie, Ciara L. Freeman, Randy D. Gascoyne, Joseph M Connors, Ryan D Morin, Laurie H. Sehn, Andrew J Mungall, Christian Steidl, David W. Scott
Journal: Blood (2022)
Meet the First Authors
Authors: Soon Chan
Journal: Circulation Research (2022)

and Engineering in KAIST, he was able to learn basic and translational research, the importance of which has been increasingly emphasized in the development of novel and clinically relevant therapeutic strategies in the field of cardiology.Dr Park continues to expand his research in the roles of endothelial cells in various cardiovascular diseases (CVDs) beyond pulmonary arterial hypertension.He also has interests in clinical research, including the association between metabolic profiles and CVDs as well as the role of imaging in CVD risk stratification.Outside of work, he enjoys hiking and spending time with his family.
Sales of Iodine-Containing Drugs in Europe Following the Beginning of the War Between Russia and Ukraine
Authors: Karel Kostev, Susanne Abeler, Ai Koyanagi, Josep Maria Haro, Lee Smith, Louis Jacob
Journal: JAMA Network Open (2022)

This cross-sectional study investigates sales of over-the-counter iodine-containing drugs in 20 European countries between January 2021 and March 2022.
Evaluation of an Intervention to Address Smoking and Food Insecurity at Preoperative Surgical Clinic Appointments
Authors: Alisha Lussiez, Alexander Hallway, Maxine Lui, Jose Perez-Escolano, Deena Sukhon, William Palazzolo, Hatim Elhady, Michael Englesbe, Ryan Howard
Journal: JAMA Network Open (2022)

Importance The health of the US population is decreasing, and novel strategies are needed to reverse the trajectory. The surgical episode may be an opportune time to screen for poor health behaviors and social needs, yet little is known about the feasibility or acceptability of such efforts. Objective To assess the feasibility and acceptability of a pilot program that engages patients in health behavior change and addresses unmet social needs at the time of surgery. Design, Setting, and, Participants This quality improvement study was conducted among 10 338 patients seen in a preoperative clinic for elective surgery between February 8 and August 31, 2021. Patients who received a referral for institutional resources were contacted via telephone to complete follow-up surveys 30 to 90 days after surgery and between July 1, 2021, and March 31, 2022. Interventions Implementation of a tool to screen patients for smoking and food insecurity in a preoperative clinic. Those who screened positive were offered referrals for institutional resources. Telephone surveys were conducted with patients who accepted referrals to understand attitudes toward addressing health behaviors and social needs. Main Outcomes and Measures Screening and referral rates, patient-perceived acceptability of addressing health behaviors and social needs at the time of surgery, smoking cessation rates, and resolution of food insecurity. Results A total of 10 338 patients (6052 women [58.5%]; mean [SD] age, 56.5 [17.9] years) were evaluated in the preoperative clinic. Of the 10 338 patients, 7825 (75.7%) were successfully screened. Of the 641 identified smokers, 152 (23.7%) accepted a referral for smoking cessation counseling. Of the 181 identified patients with food insecurity, 121 (66.9%) accepted a referral for nonmedical needs assistance. On follow-up surveys, 64 of 78 smokers (82.1%) agreed that the preoperative appointment was an appropriate time to discuss smoking cessation, and 34 of 78 smokers (43.6%) reported quitting smoking. Similarly, 69 of 84 patients with food insecurity (82.1%) agreed it was a good or very good idea for health systems to address nonmedical needs at the time of surgery, and 27 patients (32.1%) reported no longer being insecure about food since their preoperative visit. Conclusions and Relevance This study suggests that it is feasible to address patients’ foundational health at the time of surgery. Most patients agreed that these interventions were appropriate during the perioperative period. These results support using the surgical episode as an opportunity to address foundational health.
Recurrence of Symptoms Following a 2-Day Symptom Free Period in Patients With COVID-19
Authors: Davey M. Smith, Jonathan Z. Li, Carlee Moser, Eunice Yeh, Judith S. Currier, Kara W. Chew, Michael D. Hughes, Eric Daar, David Wohl, Joseph Eron, Arzhang C. Javan, Mark Giganti, Justin Ritz, Lara Hosey, Jhoanna Roa, Nilam Patel, Kelly Colsh, Irene Rwakazina, Justine Beck, Scott Seig, Courtney Fletcher, William Fischer, Teresa Evering, Rachel Bender, Sandra Cardoso, Katya Corado, Prasanna Jagannathan, Nikolaus Jilg, Alan Perelson, Sandy Pillay, Cynthia Riviere, Upinder Singh, Babafemi Taiwo, Joan Gottesman, Matthew Newell, Susan Pederson, Joan Dragavon, Cheryl Jennings, Brian Greenfelder, William Murtaugh, Jan Kosmyna, Morgan Gapara, Akbar Shahkolahi, Peter Kim, William Erhardt
Journal: JAMA Network Open (2022)

This cohort study of US adults with untreated COVID-19 examines the types and length of symptoms experienced following symptom recurrence.
Neutralizing monoclonal antibodies elicited by mosaic RBD nanoparticles bind conserved sarbecovirus epitopes
Authors: Chengcheng Fan, Alexander A. Cohen, Miso Park, Alfur Fu-Hsin Hung, Jennifer R. Keeffe, Priyanthi N.P. Gnanapragasam, Yu E. Lee, Han Gao, Leesa M. Kakutani, Ziyan Wu, Harry Kleanthous, Kathryn E. Malecek, John C. Williams, Pamela J. Bjorkman
Journal: Immunity (2022)

Increased immune evasion by SARS-CoV-2 variants of concern highlights the need for new therapeutic neutralizing antibodies. Immunization with nanoparticles co-displaying spike receptor-binding domains (RBDs) from eight sarbecoviruses (mosaic-8 RBD-nanoparticles) efficiently elicits cross-reactive polyclonal antibodies against conserved sarbecovirus RBD epitopes. Here, we identified monoclonal antibodies (mAbs) capable of cross-reactive binding and neutralization of animal sarbecoviruses and SARS-CoV-2 variants by screening single mouse B cells secreting IgGs that bind two or more sarbecovirus RBDs. Single-particle cryo-EM structures of antibody-spike complexes, including a Fab-Omicron complex, mapped neutralizing mAbs to conserved class 1/4 RBD epitopes. Structural analyses revealed neutralization mechanisms, potentials for intra-spike trimer cross-linking by IgGs, and induced changes in trimer upon Fab binding. In addition, we identified a mAb-resembling Bebtelovimab, an EUA-approved human class 3 anti-RBD mAb. These results support using mosaic RBD-nanoparticle vaccination to generate and identify therapeutic pan-sarbecovirus and pan-variant mAbs.
Functional profile of host microbiome indicates <i>Clostridioides difficile</i> infection
Authors: Etienne Nzabarushimana, Haixu Tang
Journal: Gut Microbes (2022)

Clostridioides difficile infection (CDI) is a gastro-intestinal (GI) infection that illustrates how perturbations in symbiotic host–microbiome interactions render the GI tract vulnerable to the opportunistic pathogens. CDI also serves as an example of how such perturbations could be reversed via gut microbiota modulation mechanisms, especially fecal microbiota transplantation (FMT). However, microbiome-mediated diagnosis of CDI remains understudied. Here, we evaluated the diagnostic capabilities of the fecal microbiome on the prediction of CDI. We used the metagenomic sequencing data from ten previous studies, encompassing those acquired from CDI patients treated by FMT, CDI-negative patients presenting other intestinal health conditions, and healthy volunteers taking antibiotics. We designed a hybrid species/function profiling approach that determines the abundances of microbial species in the community contributing to its functional profile. These functionally informed taxonomic profiles were then used for classification of the microbial samples. We used logistic regression (LR) models using these features, which showed high prediction accuracy (with an average AUC≥0.91), substantiating that the species/function composition of the gut microbiome has a robust diagnostic prediction of CDI. We further assessed the confounding impact of antibiotic therapy on CDI prediction and found that it is distinguishable from the CDI impact. Finally, we devised a log-odds score computed from the output of the LR models to quantify the likelihood of CDI in a gut microbiome sample and applied it to evaluating the effectiveness of FMT based on post-FMT microbiome samples. The results showed that the gut microbiome of patients exhibited a gradual but steady improvement after receiving successful FMT, indicating the restoration of the normal microbiome functions.
Retraction Notice to: Downregulation of p53-inducible microRNAs 192, 194, and 215 Impairs the p53/MDM2 Autoregulatory Loop in Multiple Myeloma Development
Authors: Flavia Pichiorri, Sung-Suk Suh, Alberto Rocci, Luciana De Luca, Cristian Taccioli, Ramasamy Santhanam, Wenchao Zhou, Don M. Benson, Craig Hofmainster, Hansjuerg Alder, Michela Garofalo, Gianpiero Di Leva, Stefano Volinia, Huey-Jen Lin, Danilo Perrotti, Michael Kuehl, Rami I. Aqeilan, Antonio Palumbo, Carlo M. Croce
Journal: Cancer Cell (2022)
Multi-omic analyses of changes in the tumor microenvironment of pancreatic adenocarcinoma following neoadjuvant treatment with anti-PD-1 therapy
Authors: Keyu Li, Joseph A. Tandurella, Jessica Gai, Qingfeng Zhu, Su Jin Lim, Dwayne L. Thomas, Tao Xia, Guanglan Mo, Jacob T. Mitchell, Janelle Montagne, Melissa Lyman, Ludmila V. Danilova, Jacquelyn W. Zimmerman, Benedict Kinny-Köster, Tengyi Zhang, Linda Chen, Alex B. Blair, Thatcher Heumann, Rose Parkinson, Jennifer N. Durham, Amol K. Narang, Robert A. Anders, Christopher L. Wolfgang, Daniel A. Laheru, Jin He, Arsen Osipov, Elizabeth D. Thompson, Hao Wang, Elana J. Fertig, Elizabeth M. Jaffee, Lei Zheng
Journal: Cancer Cell (2022)

Successful pancreatic ductal adenocarcinoma (PDAC) immunotherapy necessitates optimization and maintenance of activated effector T cells (Teff). We prospectively collected and applied multi-omic analyses to paired pre- and post-treatment PDAC specimens collected in a platform neoadjuvant study of granulocyte-macrophage colony-stimulating factor-secreting allogeneic PDAC vaccine (GVAX) vaccine ± nivolumab (anti-programmed cell death protein 1 [PD-1]) to uncover sensitivity and resistance mechanisms. We show that GVAX-induced tertiary lymphoid aggregates become immune-regulatory sites in response to GVAX + nivolumab. Higher densities of tumor-associated neutrophils (TANs) following GVAX + nivolumab portend poorer overall survival (OS). Increased T cells expressing CD137 associated with cytotoxic Teff signatures and correlated with increased OS. Bulk and single-cell RNA sequencing found that nivolumab alters CD4+ T cell chemotaxis signaling in association with CD11b+ neutrophil degranulation, and CD8+ T cell expression of CD137 was required for optimal T cell activation. These findings provide insights into PD-1-regulated immune pathways in PDAC that should inform more effective therapeutic combinations that include TAN regulators and T cell activators.
Retraction Notice to: miR-221&amp;222 Regulate TRAIL Resistance and Enhance Tumorigenicity through PTEN and TIMP3 Downregulation
Authors: Michela Garofalo, Gianpiero Di Leva, Giulia Romano, Gerard Nuovo, Sung-Suk Suh, Apollinaire Ngankeu, Cristian Taccioli, Flavia Pichiorri, Hansjuerg Alder, Paola Secchiero, Pierluigi Gasparini, Arianna Gonelli, Stefan Costinean, Mario Acunzo, Gerolama Condorelli, Carlo Maria Croce
Journal: Cancer Cell (2022)
Deep generative molecular design reshapes drug discovery
Authors: Xiangxiang Zeng, Fei Wang, Yuan Luo, Seung-gu Kang, Jian Tang, Felice C. Lightstone, Evandro F. Fang, Wendy Cornell, Ruth Nussinov, Feixiong Cheng
Journal: Cell Reports Medicine (2022)

Recent advances and accomplishments of artificial intelligence (AI) and deep generative models have established their usefulness in medicinal applications, especially in drug discovery and development. To correctly apply AI, the developer and user face questions such as which protocols to consider, which factors to scrutinize, and how the deep generative models can integrate the relevant disciplines. This review summarizes classical and newly developed AI approaches, providing an updated and accessible guide to the broad computational drug discovery and development community. We introduce deep generative models from different standpoints and describe the theoretical frameworks for representing chemical and biological structures and their applications. We discuss the data and technical challenges and highlight future directions of multimodal deep generative models for accelerating drug discovery.
The m6A reader IGF2BP2 regulates glutamine metabolism and represents a therapeutic target in acute myeloid leukemia
Authors: Hengyou Weng, Feng Huang, Zhaojin Yu, Zhenhua Chen, Emily Prince, Yalin Kang, Keren Zhou, Wei Li, Jiacheng Hu, Chen Fu, Tursunjan Aziz, Hongzhi Li, Jingwen Li, Ying Yang, Li Han, Subo Zhang, Yuelong Ma, Mingli Sun, Huizhe Wu, Zheng Zhang, Mark Wunderlich, Sean Robinson, Daniel Braas, Johanna ten Hoeve, Bin Zhang, Guido Marcucci, James C. Mulloy, Keda Zhou, Hong-Fang Tao, Xiaolan Deng, David Horne, Minjie Wei, Huilin Huang, Jianjun Chen
Journal: Cancer Cell (2022)
Reimagining antibody-dependent cellular cytotoxicity in cancer: the potential of natural killer cell engagers
Authors: Sheena Pinto, Jens Pahl, Arndt Schottelius, Paul J. Carter, Joachim Koch
Journal: Trends in Immunology (2022)

Bi-, tri- and multispecific antibodies have enabled the development of targeted cancer immunotherapies redirecting immune effector cells to eliminate malignantly transformed cells. These antibodies allow for simultaneous binding of surface antigens on malignant cells and activating receptors on innate immune cells, such as natural killer (NK) cells, macrophages, and neutrophils. Significant progress with such antibodies has been achieved, particularly in hematological malignancies. Nevertheless, several major challenges remain, including increasing their immunotherapeutic efficacy in a greater proportion of patients, particularly in those harboring solid tumors, and overcoming dose-limiting toxicities and immunogenicity. Here, we discuss novel antibody-engineering developments designed to maximize the potential of NK cells by NK cell engagers mediating antibody-dependent cellular cytotoxicity (ADCC), thereby expanding the armamentarium for cancer immunotherapy.
The duodenal mucosa associated microbiome, visceral sensory function, immune activation and psychological comorbidities in functional gastrointestinal disorders with and without self-reported non-celiac wheat sensitivity
Authors: Ayesha Shah, Seungha Kang, Nicholas J Talley, Anh Do, Marjorie M Walker, Erin R Shanahan, Natasha A Koloski, Michael P Jones, Simon Keely, Mark Morrison, Gerald J Holtmann
Journal: Gut Microbes (2022)

Frequently, patients with functional gastrointestinal disorders (FGIDs) report intolerance of wheat products. We compared gastrointestinal symptoms, sensory function, psychiatric comorbidities, gut-homing immune cells, and duodenal mucosa-associated microbiome (d-MAM) in FGID patients and controls with and without self-reported wheat sensitivity (SR-NCWS). We recruited 40 FGID patients and 20 controls referred by GPs for treatment. Gastrointestinal/extraintestinal symptoms, visceral sensory function, psychological comorbidities, and SR-NCWS were assessed in a standardized approach. Peripheral gut homing T-cells (CD4+α4+β7+CCR9+/CD8+α4+β7+CCR9+) were quantified, and the d-MAM was assessed by DNA sequencing for 46 subjects. Factors of bacterial genera were extracted utilizing factor analysis with varimax rotation and factors univariately associated with FGID or SR-NCWS included in a subsequent multivariate analysis of variance to identify statistically independent discriminators. Anxiety scores (p < .05) and increased symptom responses to a nutrient challenge (p < .05) were univariately associated with FGID. Gut homing T-cells were increased in FGID patients with SR-NCWS compared to other groups (p all <0.05). MANOVA revealed that anxiety (p = .03), visceral sensory function (p = 0.007), and a d-MAM factor comprise members of the Alloprevotella, Prevotella, Peptostreptococcus, Leptotrichia, and Veillonella lineages were significantly (p = .001) associated with FGID, while gut homing CD4+α4+ β7+CCR9+ T-cells were associated (p = .002) with SR-NCWS. Compared to controls, patients with and without SR-NCWS show that there are shifts in the amplicon sequence variants within specific bacterial genera between the FGID subgroups (particularly Prevotella and Streptococcus) as well as distinct bacterial taxa discriminatory for the two different FGID subtypes. Compared to controls, both FGID patients with and without SR-NCWS have an increased symptom response to a standardized nutrient challenge and increased anxiety scores. The FGID patients with SR-NCWS – as compared to FGID without SR-NCWS (and controls without SR-NCWS) – have increased gut homing T-cells. The d-MAM profiles suggest species and strain-based variations between the two FGID subtypes and in comparison to controls.